Effects of Amlodipine and Other Blood Pressure Lowering Agents on Microvascular Function

NCT03082014 | Terminated Phase 3

• 1 other identifier: TRE-1486--0105-I
• Study Type: interventional
• Target: 101
• Locations: 3 countries
• Sites: 5

Brief Summary

Multicentre, multinational, prospective randomised, open-label, 3 sequence crossover phase III b clinical trial with blinded endpoint assessment (PROBE-design)

• in 75 patients with sporadic small vessel diseases (SVDs) and
• in 30 patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Conditions

Cerebral Small Vessel Diseases

Keywords

Hypertension; Cerebrovascular Reactivity; Blood Pressure Variability

Outcome Measures

Primary Outcomes (1)

• Change from Baseline Cerebrovascular Reactivity (CVR) at 4 weeks of Monotherapy

  The primary outcome variable is CVR as determined by blood oxygen level-dependent (BOLD) MRI (T2\*) brain scan response to hypercapnic challenge at the end of the 2 week run-in phase and after 4 weeks of monotherapy while still on medication.

  baseline measure at the end of the run-in phase (week 2); after 4 weeks of each monotherapy (week 6, week 10, and week 14)

Secondary Outcomes (2)

• Change from Baseline Mean Systolic Blood Pressure (SBP) at the last week of each treatment phase

  within the last week of the run-in phase and within the last week of each treatment phase

• Change from Baseline Blood Pressure Variability (BPv) at the last week of each treatment phase

  within the last week of the run-in phase and within the last week of each treatment phase

Study Arms (3)

Arm A

ACTIVE COMPARATOR

Amlodipine for 4 weeks, Losartan for 4 weeks, Atenolol for 4 weeks.

Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

Arm B

ACTIVE COMPARATOR

Atenolol for 4 weeks, Amlodipine for 4 weeks, Losartan for 4 weeks.

Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

Arm C

ACTIVE COMPARATOR

Losartan for 4 weeks, Atenolol for 4 weeks, Amlodipine for 4 weeks.

Drug: Amlodipine; Drug: Losartan; Drug: Atenolol

Interventions

Amlodipine DRUG

blood pressure lowering agent - dihydropyridine Ca2+-channel blocker

Arm A; Arm B; Arm C

Losartan DRUG

blood pressure lowering agent - angiotensin-receptor blockers

Arm A; Arm B; Arm C

Atenolol DRUG

blood pressure lowering agent - beta-blocker

Arm A; Arm B; Arm C

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients may be enrolled in the trial if all of the following criteria have been met:
• Symptomatic SVD defined as
• History of clinical lacunar stroke in the last 5 years with a corresponding small subcortical infarct visible on MRI scan or CT scan\* compatible with the clinical syndrome.
• \*On MRI, recent infarct is defined as a diffusion-weighted imaging (DWI) lesion on the acute MRI scan. On CT, recent infarct is defined as a novel infarct on CT within 3 weeks after the event that was not visible on the admission CT. Patients admitted to the hospital with an obvious lacunar syndrome and an admission CT/CT perfusion compatible with a lacunar infarct but without an MRI in the (sub)acute stage and no repeat CT performed in the context of clinical care can be recruited for TREAT-SVDs. After providing informed consent they will be invited for the screening visit including a 3T MRI. The 3T MRI will be used to verify the presence of a new lesion, relative to the admission CT, compatible with a lacunar infarct and compatible with the lacunar syndrome. If such a lesion is present the patient will undergo the further TREAT-SVDs workup. If no such lesion is observed the patient will be excluded from the study and considered as a screening failure.
• or cognitive impairment defined as visiting a memory clinic with cognitive complaints, objective cognitive impairment\*, and capacity to consent, and with confluent deep white matter hyperintensities (WMH) on MRI (defined on the Fazekas scale as deep WMH score ≥ 2)
• \*concluded by the treating physician based on a validated cognitive measurement tool (for example but not limited to MoCA or CAMCOG)
• or a diagnosis of CADASIL established by molecular genetic testing of the NOTCH3 gene (presence of an archetypical, cysteine-affecting mutation) or the presence of granular osmiophilic material in ultrastructural, electron microscopy analysis of skin biopsy
• Indication for antihypertensive treatment (as defined by meeting one of the following):
• Hypertension defined as SBP ≥ 140 mmHg or diastolic BP (DBP) ≥ 90 mmHg without antihypertensive treatment or use of an antihypertensive drug for previously diagnosed hypertension
• Prior history of stroke or transient ischaemic attack (TIA)
• Age 18 years or older
• Written informed consent

You may not qualify if:

• Patients will be excluded from the trial for any of the following reasons:
• Unwillingness or inability to give written consent
• Pregnant or breastfeeding women, women of childbearing age not taking contraception.
• Acceptable contraception in women of childbearing age is a "highly effective" contraceptive measure as defined by the Clinical Trials Facilitation Group and includes combined (oestrogen and progesterone containing) or progesterone-only contraception associated with inhibition of ovulation, or intrauterine device, or bilateral tubal occlusion.
• Contraindications to MRI (pacemaker, aneurysm clip, cochlear implant etc.)
• Other major neurological or psychiatric conditions affecting the brain and interfering with the trial design (e.g. multiple sclerosis)
• In case of clinical lacunar stroke syndrome other causes of stroke such as
• ≥ 50% luminal stenosis (NASCET) in large arteries supplying the area of ischaemia
• major-risk cardioembolic source of embolism (permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumours, mitral stenosis, recent (\< 4 weeks) myocardial infarction, left ventricular ejection fraction less than 30%, valvular vegetations, or infective endocarditis)
• other specific causes of stroke identified (e.g. arteritis, dissection, migraine/vasospasm, drug misuse)
• Other stroke risk factor requiring immediate intervention that would preclude involvement in the trial
• Renal impairment (eGFR \< 35ml/min)
• Life expectancy \< 2 years
• Use of \> 2 antihypertensive drugs at maximum dose or equivalent (one drug at the maximum dose and two drugs at half of the maximum dose) for an appropriate BP control
• Contraindications to the applied antihypertensive drugs as known

Sponsors & Collaborators

• Ludwig-Maximilians - University of Munich: lead
• University of Edinburgh: collaborator
• Maastricht University Medical Center: collaborator
• UMC Utrecht: collaborator
• University of Oxford: collaborator

Study Sites (5)

Insitute for Stroke and Dementia Research

Munich, 81377, Germany

Location

Maastricht University Medical Center

Maastricht, 6202 AZ, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Nuffield Department of Clinical Neurosciences

Oxford, England, OX1 2JD, United Kingdom

Location

Centre for Clinical Brain Sciences

Edinburgh, Scotland, EH16 4SB, United Kingdom

Location

Related Publications (2)

• Kopczak A, Stringer MS, van den Brink H, Kerkhofs D, Blair GW, van Dinther M, Reyes CA, Garcia DJ, Onkenhout L, Wartolowska KA, Thrippleton MJ, Kampaite A, Duering M, Staals J, Lesnik-Oberstein S, Muir KW, Middeke M, Norrving B, Bousser MG, Mansmann U, Rothwell PM, Doubal FN, van Oostenbrugge R, Biessels GJ, Webb AJS, Wardlaw JM, Dichgans M; TREAT-SVDs collaborators. Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial. Lancet Neurol. 2023 Nov;22(11):991-1004. doi: 10.1016/S1474-4422(23)00293-4.

  PMID: 37863608 DERIVED

• Kopczak A, S Stringer M, van den Brink H, Kerkhofs D, W Blair G, van Dinther M, Onkenhout L, A Wartolowska K, Thrippleton MJ, Duering M, Staals J, Middeke M, Andre E, Norrving B, Bousser MG, Mansmann U, Rothwell PM, N Doubal F, van Oostenbrugge R, Biessels GJ, Webb AJ, Wardlaw JM, Dichgans M. The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial. Eur Stroke J. 2023 Mar;8(1):387-397. doi: 10.1177/23969873221143570. Epub 2022 Dec 16.

  PMID: 37021189 DERIVED

MeSH Terms

Conditions

Cerebral Small Vessel Diseases; Hypertension

Interventions

Amlodipine; Losartan; Atenolol

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Biphenyl Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Imidazoles; Azoles; Tetrazoles; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Propanols; Amines

Study Officials

• Martin Dichgans, Prof.

  Institute for Stroke and Dementia Research

  STUDY DIRECTOR

• Joanna Wardlaw, Prof.

  Neuroimaging Sciences and Brain Research Imaging Centre

  PRINCIPAL INVESTIGATOR

• Robert van Oostenbrugge, Prof.

  Maastricht University Medical Center (UM), Department of Neurology

  PRINCIPAL INVESTIGATOR

• Geert Jan Biessels, Prof.

  UMC Utrecht Brain Center Robert Magnus (UMCU)

  PRINCIPAL INVESTIGATOR

• Peter Rothwell, Prof.

  Nuffield Department of Clinical Neurosciences, Oxford (UOXF)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Cerebrovascular reactivity measures will be assessed centrally by a blinded rater.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Martin Dichgans

Model Details: TREAT-SVDs is a multi-centre, multinational phase III b clinical trial with a three sequence crossover design. It will be carried out as a rater blinded trial which is also known as PROBE-design (prospective, randomised, open-label trial with blinded endpoint assessment).

Study Record Dates

• First Submitted: March 8, 2017
• First Posted: March 17, 2017
• Study Start: February 22, 2018
• Primary Completion: July 28, 2022
• Study Completion: July 28, 2022
• Last Updated: March 9, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2); GB (2); DE (1)